Sickle cell anemia (SCA) is the paradigmatic monogenic disease, but the sickle mutation is not sufficient to define the phenotype. Pleiotropic effects influence complications. Secondly, SCA exhibits an intense inter-individual variability, which is likely to be the effect of epistatic genes, since heritability of major determinants of severity exhibit high concordance in monozygote twins (89%). The aim of this project is to define the epistatic/pleiotropic genes involved in sickle-cell mediated vaso-occlusion in different organs, building on our years of working on the genetics and pathophysiology of this problem in mice and men. We will engage in the detection of genes involved in sickle cell-mediated vaso-occlusion in animal models, in the detection of genes involved in sickle cell-mediated vaso-occlusion in patients with sickle cell anemia and in the detection of genes involved in vaso-occlusive and vaso-proliferative processes in sickle cell retina and choroid and in cerebrovascular complications in sickle cell anemia, which our previous work has defined as a special case. The experimental design is the following: Approach 1: Appropriate tissues in sickle transgenic mice and other animal models -+ RNA -+ expression chips -> select the higher express genes and the lower expressing genes vs control -+ BLAST --> the selected human genes will be analyzed for potential epistatic effects by SNP arrays and by sequencing to define polymorphism in appropriately defined human sickle cell anemia DNA samples. Approach 2: In the complications without animal models, but candidate genes based on human pathophysiological data, SNPs and sequencing analyzes will be performed in sickle cell anemia patients with a particular complication vs sickle cell anemia patients without it. Of course, appropriate matching age groups will be selected to assure that the complication is no longer possible in the control group. Genes defined by these two approaches will be followed in animal models when available (KO or over expression, or generated for further confirmation. Members of this proposal have special expertise in retinal, cerebro-vascular problems and statistical analysis. Our institution has well established expertise in transgenic mice, microcirculatory preparations, hemopoiesis and patient follow-up, as a well as experienced SNP, sequencing and CHIP expression facilities.